Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial

Abstract

Aims: We studied the unclear question whether blood pressure (BP) lowering reduces cardiovascular disease (CVD) in elderly individuals with systolic BP <160 mm Hg.

Methods and results: We initiated a randomized placebo-controlled stratified 2 × 2 factorial clinical trial evaluating the effects of BP lowering in 11 000 elderly individuals with systolic blood pressure (SBP) between 130 and 159 mm Hg, for 5 years. Following 5-week active run-in, participants were randomized to aliskiren (300 mg) or placebo, and to an additional antihypertensive [hydrochlorothiazide (25 mg) or amlodipine (5 mg)], or their respective placeboes. Study was terminated by sponsor after 1759 subjects (age 72.1 ± 5.2 years, 88% receiving at least one antihypertensive) were randomized and followed for 0.6 year. Study drugs were well tolerated with few serious adverse events during run-in and after randomization, with no significant differences between treatment groups. By design, three levels of BP reductions were achieved, adjusted mean BP reductions of 3.5/1.7 mm Hg (P < 0.001) by aliskiren, 6.8/3.3 mm Hg (P < 0.001) by hydrochlorothiazide or amlodipine, and 10.3/5.0 mm Hg (P < 0.001) by double therapy compared with placebo. Twenty-five major CVD events occurred. Non-significant trends towards fewer CVD events with greater BP reductions are evident: hazard ratios (HR) 0.82 [95% confidence interval (CI): 0.37-1.81] for 3.5 mm Hg SBP reduction; HR 0.45 (95% CI: 0.19-1.04) for 6.8 mm Hg; and HR 0.25 (0.05-1.18) for 10.3 mm Hg reduction for primary composite of CV death, MI, stroke, or significant heart failure.

Conclusions: Sizeable reductions in BP, with potential for substantial CVD reduction, can be safely achieved using combinations of BP drugs in the elderly with normal high and Stage 1 hypertension.

Clinical trial registration: NCT01259297.

Keywords: Aliskiren; Clinical trial; Combination therapy; Direct renin inhibitor; Lowering stage 1 hypertension in elderly.

Figure 1

Recruitment flow chart.

Figure 2

Mean (95% confidence interval) differences (mm Hg) in SBP and DBP between active and placebo treatments (alikiren vs. placebo, hydrochlorothiazide, or amlodipine vs. placebo and double therapy vs. double placebo. Mean blood pressure between blood pressure at run-in and average blood pressure after randomization (Week 6 and Month 6 measurements) were compared.

Figure 3

Clinical composite outcomes (hazard ratios and 95% confidence interval) by treatment (aliskiren vs. placebo, hydrochlorothiazide/amlodipine vs. placebo and double therapy vs. double placebo) for the (1) primary composite outcome of CV death, MI, stroke and significant heart failure and (2) the composite of all-cause mortality, MI, stroke and significant heart failure. Due to small number of events, no significant differences were found between each of the treatments but consistent trends towards reduced event rates with active treatment were observed.